The heritability of alcoholism is 40-60% in both men and women, however, as in other complex psychiatric diseases, it has proved difficult to identify causative genes. Intermediate phenotypes are associated biological traits that may be influenced by variation at fewer genes and may mediate different aspects of the disease. The intermediate phenotypes we are studying include dimensional anxiety (harm avoidance (HA)), resting EEG phenotypes, event-related potentials (ERPs) and heart rate variability (HRV). We have three large intermediate phenotype datasets: 247 US Caucasians, 365 Plains American Indians with a high prevalence of alcoholism and 198 Southeastern American Indians with a low prevalence of alcoholism. We have identified an intermediate phenotype for alcoholism vulnerability, the low voltage alpha (LVA) EEG, a normal, traitlike heritable variant of the resting EEG, present in 7-14% of the population, in which the alpha rhythm is virtually absent. We have shown that LVA is associated with alcoholism, particularly when accompanied by anxiety disorders (Enoch et al 1995,1999). Moreover, we found that LVA individuals, irrespective of clinical state, had reduced auditory and visual P300 ERP amplitudes, further strengthening our argument for the association of LVA with alcoholism vulnerability (Enoch et al 2002). As expected, P300 amplitude was reduced in alcoholics, however, it was lowest in alcoholics with comorbid anxiety disorders (Enoch et al 2001). [unreadable] [unreadable] We are undertaking candidate gene analyses and have found that in both Caucasian and Plains Indian women, the low activity Met allele (and particularly the Met/Met homozygote) of the catechol-O-methyltransferase (COMT) Val158Met functional polymorphism is associated both with LVA and HA (Enoch et al, 2003). Moreover, in this tribe the COMT Met/Met genotype is protective against alcoholism and the Met158 allele is protective against smoking in women (Enoch et al, 2006). We have also found that LVA is associated with the DRD2 functional promoter polymorphism, -141CIns/Del. We have recently found associations between HA and BDNF functional variants (Jiang et al, 2005) and between alcoholism, mediated by HA, and an HNMT functional variant (Oroszi et al, 2005, Reuter et al, 2006). Recent analyses have shown that there may be two vulnerability factors for anxiety disorders with differing genetic susceptibility (HTTLPR, COMT Val158Met, BDNF Val66Met): (a) heightened attention (increased P300 amplitude) and better working memory with mildly elevated anxiety-neuroticism; a constellation that may be protective against other psychopathology, and (b) poorer attention and working memory with greater anxiety-neuroticism; a constellation that may also increase vulnerability to alcoholism and major depression (Enoch et al, submitted).[unreadable] [unreadable] Our recent, high-density whole genome linkage scan in the Plains Indians has identified a convergence of resting EEG phenotypes (alpha and beta power at frontal and posterior leads) to a chromosome 5 region within which fewer than 20 first-line candidate genes are located. Preliminary analyses have shown an association of EEG power with corticotrophin releasing hormone binding protein (CRHBP), a gene that is implicated in stress and addiction. Further analyses are underway. [unreadable] [unreadable] Formerly titled "Genetic studies of the electroencephalogram and event-related potentials" and "Genetic studies of EEG and ERP traits related to alcoholism".